HLA Genotype and Probiotics Modify the Association Between Timing of Solid Food Introduction and Islet Autoimmunity in the TEDDY Study

Abstract

Objective: To study the interaction among HLA genotype, early probiotic exposure, and timing of complementary foods in relation to risk of islet autoimmunity (IA).

Research design and methods: The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively follows 8,676 children with increased genetic risk of type 1 diabetes. We used a Cox proportional hazards regression model adjusting for potential confounders to study early feeding and the risk of IA in a sample of 7,770 children.

Results: Any solid food introduced early (<6 months) was associated with increased risk of IA if the child had the HLA DR3/4 genotype and no probiotic exposure during the 1st year of life. Rice introduced at 4-5.9 months compared with later in the U.S. was associated with an increased risk of IA.

Conclusions: Timing of solid food introduction, including rice, may be associated with IA in children with the HLA DR3/4 genotype not exposed to probiotics. The microbiome composition under these exposure combinations requires further study.

Graphical abstract

Figure 1

Timing of the introduction of foods and the risk of developing any IA, IAA-first, GADA-first, and multiple autoantibodies by HLA genotype and by probiotic exposure by 52 weeks of age, showing only the statistically significant associations. The HR from the Cox proportional hazard model (with 95% CI) uses the reference of ≥6 months, except >9 months for egg. Dark-colored arrows flag P < 0.05, and light-colored arrows flag 0.05 < P < 0.09. Statistically significant three-way interactions between HLA genotype, timing of probiotic exposure, and timing of gluten cereals introduction: P = 0.034 for any IA and P = 0.019 for GADA-first, and between HLA genotype, timing of probiotic exposure, and timing of egg introduction: P = 0.023 for multiple autoantibodies.